Metallothionein 2A-Silencing Antimonene-Based Nanoagonist for Amplifying the Photothermal Immunotherapy of Gynecologic Malignancy

Abstract

Gynecologic malignancies are prone to metastasis and recurrence due to the low efficacy and sensitivity of current clinical treatments. Here, we construct ultrasmall Sb@Au nanodots (Sb@Au NDs) as a metallothionein 2A (MT 2A)-silencing nanoagonist for effective photothermal immunotherapy of gynecologic malignancies. Sb@Au NDs show high photothermal conversion efficiency of 56.8% under a 1270 nm laser and exceptional capability for downregulating MT 2A overexpressed in gynecologic malignancies. Synergizing mild photothermal therapy (PTT) with targeting downregulation of MT 2A based on Sb@Au NDs offers a robust therapeutic effect, significantly activating adaptive immune response and inhibiting the metastasis of gynecologic malignancies. RNA sequencing results of SKOV-3 cells elucidate that MT 2A downregulation by Sb@Au NDs impedes the transcription of zinc finger protein genes, thereby triggering the TGF-β signaling pathway, which blocks the cell cycle and activates the MAPK/c-fos apoptotic pathway to sensitize the treatment of gynecologic malignancies. Mild PTT synergizing with MT 2A downregulation by Sb@Au NDs can promote the secretion of β-defensin to increase the infiltration of CD4⁺ and CD8⁺ T cells and potentiate T-cell-mediated adaptive immune response. Our work provides an MT 2A-silencing nanoagonist for highly effective combination therapy and metastasis inhibition of gynecologic malignancies.